Our research includes human, population, and evolutionary genetics, with particular emphasis on study of the HLA region, the major histocompatibility complex (MHC) of humans. The genes of the HLA region control several different functions involved inthe immune response. They also influence susceptibility to over 200 diseases, including autoimmune diseases, cancers, and infectious diseases. A number of functional and population features implicate selection as an important factor maintaining the extensive HLA variation. Although the precise nature of this selection is not known, response to a wide variety of pathogens is believed to be a major evolutionary pressure. Recent advances in genomics, combined with increasing knowledge of structure-function of MHC molecules, provides new tools for exploring HLA polmorphism and an opportunity to address fundamental questions about HLA sequence variation, immunity, and disease. Such detailed information has not previously been available and is critical for a complete understanding of the immune system, autoimmune and infectious diseases, transplantation, and development of T-cell therapies and vaccines. Our major goal is to advance knowledge of the evolutionary factors maintaining the genetic diversity of the HLA classical genes, particularly the selective forces acting, and specifically to identify amino acid sites, and combinations of sites, critically involved in HLA regulated immune responses and in disease predisposition/protection. Our research methodology involved theoretical modeling, computer simulation, molecular biology, and hypothesis testing of genetic data. Theoretical and statistical methods developed in our study of HLA variation have applicability to any polymorphic marker system in humans and other species. Our research will also include genome-wide analyses, given that access to such data will increasingly be available. Characterization of genetic variation across the human genome, including comparison with HLA region data, is essential for mapping complex disease genes, identifying genomic regions that have undergone recent selection, and understanding the origin, maintenance, and evolution of genetic variation in human populations, including variation involved in disease processes.